Stuttering has long been known to have a genetic component. We have recently identified mutations in the GNPTAB gene that occur in individuals who stutter but do not occur in normal controls. Based on these results, we went on to identify mutations in two genes that function in the same biochemical pathway, GNPTG and NAGPA. Together these results indicate that stuttering can be associated deficits in the lysosomal targeting pathway. A goal of our current research is to identify how the subtle metabolic defects caused by mutations in these three genes lead to stuttering without any other discernible symptoms. In initial studies designed to localize the site of the pathology involved, we are measuring the level of expression of these three genes in 27 different regions of the human brain. We are also working to develop a mouse model of human stuttering. This is being done by creating so-called knock-in strains of mice that carry the mutations identified in humans who stutter. These experiments require a detailed acoustical analysis of mouse vocalization, which is largely ultrasonic in nature. In these experiments, we are working with Drs. Terra Barnes and Tim Holy at Washington University in St. Louis, who are leaders in the study of mouse vocalization. In a parallel line of inquiry, we are working with Dr. Stuart Kornfeld, also at Washington University in St. Louis. Dr. Kornfeld is a world leader in the study of the enzymes encoded by the GNPTAB, GNPTG, and NAGPA genes. The goal of these studies is to better understand the effects of the mutations observed in human stutterers on the function of these enzymes at the molecular and cellular level. Initial results in our analysis of mutations of the NAGPA gene found in stuttering indicate that these mutations reduce the activity of this enzyme by about half, and cause it to be mis-localized and/or more rapidly degraded than the normal version of this enzyme. In the past year we have continued our studies in a group of families from Cameroon, West Africa, which each have many cases of persistent stuttering. Our studies of the largest of these families have shown that there is more than one causative gene (at more than one location) at work in this large family, and we have identified significant linkage on chromosomes 2, 3, 14, and 15. Additional studies in stuttering families from Brazil have identified a new stuttering gene localization on chromosome 10. We are working to refine these gene locations, and to identify the specific causative genes at each of these locations. We believe that identification of genes that contribute to persistent stuttering will provide important new information about the causes of stuttering, which may lead to improved diagnosis and treatment of this disorder. Our studies of taste perception are focused on the role of genetic differences in taste perception in tobacco use, particularly the use of mentholated cigarettes, which are disproportionately used by African Americans. Our goal is to determine whether this disproportionate use is associated with genetic differences, specific to African Americans, in genes that encode taste perception machinery. This study is being done in collaboration with the University of Texas Southwestern Medical Center, using the well-characterized Dallas Heart Study population.